The present invention is directed to the treatment of acute and chronic inflammatory responses, for example resulting from the presence of an allergen, injury, infection, etc. Allergic and acute inflammatory responses to injury, infection, or other tissue damage can set into motion a complex series of events. A variety of host cells that guard the host environment interface, including macrophages, mast cells, and epithelial/epidermal cells serve as the initiators of the inflammatory responses. These cells release various mediators during an inflammatory response, which include histamine, prostaglandins (PGs), leukotrienes (LTs) and proinflammatory cytokines (refs 1-4). These mediators have been implicated in the pathogenesis of a number of acute and chronic inflammatory conditions such as allergy, asthma, arthritis, psoriasis, and skin sunburn (refs 3-5).
The release of inflammatory agents is mediated by a cascade of intracellular signaling events which include activation of phosphoinositide turnover (ref 6), increase in cAMP levels (ref 7), activation of protein kinase C, and an increase in intracellular calcium levels and tyrosine phosphorylation of several cytosolic proteins (refs 7 and 8). Considerable efforts have been made for identification of chemical compounds that can interrupt these signaling events as potential anti-inflammatory agents (refs 9-12). However, the need for agents providing improved inhibition continues.